Pharmacophore Modeling and Docking Studies to Investigate Potential Leads for the Development of β -Secretase APP Cleavage Enzyme-1 (BACE-1) Inhibitors

Author(s): Richa Arya, Satya Prakash Gupta*, Sarvesh Paliwal, Swapnil Sharma, Kirtika Madan, Monika Chauhan.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 7 , 2019

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Abstract:

Background: Alzheimer’s disease is a medical condition with detrimental brain health. It is majorly diagnosed in aging individuals plaque in β) characterized by accumulated Amyloidal beta (A 1 BACE) 1 secretase APP cleavage enzyme βneurological areas. The ) is the target of choice that can be exploited to find drugs against Alzheimer’s disease.

Methods: A series of BACE-1 inhibitors with reported binding constant were considered for the development of a feature based pharmacophore model.

Results: The good correlation coefficient (r=0.91) and RMSD of 0.93 was observed with 30 compounds in training set. The model was validated internally (r2test=0.76) as well as externally by Fischer validation. The pharmacophore based virtual screening retrieved compounds that were docked and biologically evaluated.

Conclusion: The three structurally diverse molecules were tested by in-vitro method. The pyridine derivative with highest fit value (6.9) exhibited IC50 value of 2.70 µM and thus was found to be the most promising lead molecule as BACE-1 inhibitor.

Keywords: β-secretase APP cleavage enzyme-1, β-secretase, docking, fluorescence, micro plate, pharmacophore, virtual screening.

[1]
Watson, D.; Castaño, E.; Kokjohn, T.A.; Kuo, Y.M.; Lyubchenko, Y.; Pinsky, D.; Connolly, E.S.; Esh, C.; Luehrs, D.C.; Stine, W.B.; Rowse, L.M. Physicochemical characteristics of soluble oligomeric A β and their pathologic role in Alzheimer’s disease. Neurol. Res., 2005, 27, 869-881.
[2]
Lichtenthaler, S.F. Alpha-secretase in Alzheimer’s disease: Molecular identity, regulation and therapeutic potential. J. Neurochem., 2011, 116, 10-21.
[3]
Vassar, R.; Bennett, B.D.; Babu-Khan, S.; Kahn, S.; Mendiaz, E.A.; Denis, P.; Teplow, D.B.; Ross, S.; Amarante, P.; Loeloff, R.; Luo, Y. β-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science, 1999, 286, 735-741.
[4]
Luo, Y.; Bolon, B.; Kahn, S.; Bennett, B.D.; Babu-Khan, S.; Denis, P.; Fan, W.; Kha, H.; Zhang, J.; Gong, Y.; Martin, L. Mice deficient in BACE1, the Alzheimer’s β-secretase, have normal phenotype and abolished β-amyloid generation. Nat. Neurosci., 2001, 4, 231-232.
[5]
Roberds, S.L.; Anderson, J.; Basi, G.; Bienkowski, M.J.; Branstetter, D.G.; Chen, K.S.; Freedman, S.B.; Frigon, N.L.; Games, D.; Hu, K.; Johnson-Wood, K.; Kappenman, K.E.; Kawabe, T.T.; Kola, I.; Kuehn, R.; Lee, M.; Liu, W.; Motter, R.; Nichols, N.F.; Power, M.; Robertson, D.W.; Schenk, D.; Schoor, M.; Shopp, G.M.; Shuck, M.E.; Sinha, S.; Svensson, K.A.; Tatsuno, G.; Tintrup, H.; Wijsman, J.; Wright, S.; Mc Conlogue, L. BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: Implications for Alzheimer’s disease therapeutics. Hum. Mol. Genet., 2001, 10, 1317-1324.
[6]
Grill, J.D.; Cummings, J.L. Novel targets for Alzheimer’s disease treatment. Expert Rev. Neurother., 2010, 10, 711.
[7]
Jeppsson, F.; Eketjäll, S.; Janson, J.; Karlström, S.; Gustavsson, S.; Olsson, L.L.; Radesäter, A.C.; Ploeger, B.; Cebers, G.; Kolmodin, K.; Swahn, B.M.; VonBerg, S.; Bueters, T.; Fälting, J. Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J. Biol. Chem., 2012, 287, 41245-41257.
[8]
Probst, G.; Xu, Y.Z. Small-molecule BACE1 inhibitors: A patent literature review (2006-2011). Expert Opin. Ther. Pat., 2012, 22, 511-540.
[9]
Wallace, J. Combination of levetiracetam and a beta-secretase (BACE) inhibitor. U.S. Patent 6, 213, 645, July 28 2016.
[10]
Rogawski, M.A.; Wenk, G.L. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev., 2003, 9, 275-308.
[11]
Francis, P.T.; Palmer, A.M.; Snape, M.; Wilcock, G.K. The cholinergic hypothesis of Alzheimer’s disease: A review of progress. J. Neurol. Neurosurg. Psychiatry, 1999, 66, 137-147.
[12]
Lu, S.H.; Wu, J.W.; Liu, H.L.; Zhao, J.H.; Liu, K.T.; Chuang, C.K.; Lin, H.Y.; Tsai, W.B.; Ho, Y. The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies. J. Biomed. Sci., 2011, 18, 8.
[13]
Yang, S.Y. Pharmacophore modeling and applications in drug discovery: Challenges and recent advances. Drug Discov. Today, 2010, 15, 444-550.
[14]
Cumming, J.; Babu, S.; Huang, Y.; Carrol, C.; Chen, X.; Favreau, L.; Greenlee, W.; Guo, T.; Kennedy, M.; Kuvelkar, R.; Le, T.; Li, G.; Mc Hugh, N. Orth, P.; Ozgur, L.; Parker, E.; Saionz, K.; Stamford, A.; Strickland, C.; Tadesse, D.; Voigt, J.; Zhang, L.; Zhang, Q. Piperazine sulfonamide BACE1 inhibitors: Design, synthesis, and in vivo characterization. Bioorg. Med. Chem. Lett., 2010, 20, 2837-2842.
[15]
Yue-Dong, G.A.; Jing-Fei, H.U. An extension strategy of discovery studio 2.0 for non-bonded interaction energy automatic calculation at the residue level. Dongwuxue Yanjiu, 2011, 32, 262-266.
[16]
Chen, C.Y. Discovery of novel inhibitors for c-Met by virtual screening and pharmacophore analysis. J. Chin. Inst. Chem. Eng, 2008, 39, 617-624.
[17]
Yu, H.; Wang, Z.; Zhang, L.; Zhang, J.; Huang, Q. The discovery of novel vascular endothelial growth factor receptor tyrosine kinases inhibitors: Pharmacophore modeling, virtual screening and docking studies. Chem. Biol. Drug Des., 2007, 69, 204-211.
[18]
Chen, C.Y. Weighted equation and rules-a novel concept for evaluating protein-ligand interaction. J. Biomol. Struct. Dyn., 2009, 2, 271-282.
[19]
Sakkiah, S.; Thangapandian, S.; John, S.; Kwon, Y.J.; Lee, K.W. 3D QSAR pharmacophore based virtual screening and molecular docking for identification of potential HSP90 inhibitors. Eur. J. Med. Chem., 2010, 45, 2132-2140.
[20]
Kirchmair, J.; Markt, P.; Distinto, S.; Wolber, G.; Langer, T. Evaluation of the performance of 3D virtual screening protocols: RMSD comparisons, enrichment assessments, and decoy Selection-What can we learn from earlier mistakes? J. Comput. Aided Mol. Des., 2008, 22, 213-228.
[21]
Topliss, J.G.; Costello, R.J. Chance correlations in structure-activity studies using multiple regression analysis. J. Med. Chem., 1979, 22, 1238-1244.
[22]
Ghose, A.K.; Viswanadhan, V.N.; Wendoloski, J.J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem., 1999, 1, 55-68.
[23]
Abdula, A.M.; Khalaf, R.A.; Mubarak, M.S.; Taha, M.O. Discovery of new β‐D‐galactosidase inhibitors via pharmacophore modeling and QSAR analysis followed by in silico screening. J. Comput. Chem., 2011, 32, 463-482.
[24]
Viswanadhan, V.N.; Balan, C.; Hulme, C.; Cheetham, J.C.; Sun, Y. Knowledge-based approaches in the design and selection of compound libraries for drug discovery. Curr. Opin. Drug Discov. Devel., 2002, 5, 400-406.
[25]
Kalita, J.M.; Ghosh, S.k.; Sahu, S.; Dutta, M. A statistical analysis to find out an appropriate docking method. Asian J. Pharm. Clin. Res, 2015, 7, 158-160.
[26]
Lang, H.; Huang, X.; Yang, Y. Identification of putative molecular imaging probes for BACE-1 by accounting for protein flexibility in virtual screening. J. Alzheimers Dis., 2012, 29, 351-359.
[27]
Clarke, B.; Cutler, L.; Demont, E.; Dingwall, C.; Dunsdon, R.; Hawkins, J.; Howes, C.; Hussain, I.; Maile, G.; Matico, R.; Mosley, J. BACE-1 hydroxyethylamine inhibitors using novel edge-to-face interaction with Arg-296. Bioorg. Med. Chem. Lett., 2010, 20, 4639-4644.
[28]
Xu, Y.; Li, M.J.; Greenblatt, H.; Chen, W.; Paz, A.; Dym, O.; Peleg, Y.; Chen, T.; Shen, X.; He, J.; Jiang, H.; Silman, I.; Sussman, J.L. Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and MD simulations. Acta Crystallogr. D Biol. Crystallogr., 2012, 68, 13-25.
[29]
Roy, K.; Paul, S. Docking and 3D-QSAR studies of acetohydroxy acid synthase inhibitor sulfonylurea derivatives. J. Mol. Model., 2010, 16, 951-964.
[30]
Ewing, T.J.; Kuntz, I.D. Critical evaluation of search algorithms for automated molecular docking and database screening. J. Comput. Chem., 1997, 18, 1175-1189.
[31]
Koska, J.; Spassov, V.Z.; Maynard, A.J.; Yan, L.; Austin, N.; Flook, P.K.; Venkatachalam, C.M. Fully automated molecular mechanics based induced fit protein-ligand docking method. J. Chem. Inf. Model., 2008, 48, 1965-1973.
[32]
Kennedy, M.E.; Wang, W.; Song, L.; Lee, J.; Zhang, L.; Wong, G.; Wang, L.; Parker, E. Measuring human β-secretase (BACE1) activity using homogeneous time-resolved fluorescence. Anal. Biochem., 2003, 319, 49-55.
[33]
Garino, C.; Pietrancosta, N.; Laras, Y.; Moret, V.; Rolland, A.; Quéléver, G.; Kraus, J.L. BACE-1 inhibitory activities of new substituted phenyl-piperazine coupled to various heterocycles: Chromene, coumarin and quinoline. Bioorg. Med. Chem. Lett., 2006, 16, 1995-1999.


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Article Details

VOLUME: 16
ISSUE: 7
Year: 2019
Page: [775 - 784]
Pages: 10
DOI: 10.2174/1570180815666181023110736
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